We are investigating how a GPCR chemosensing network regulates the polarized reorganization of the actin cytoskeleton required for protrusion of the cell's front and retraction of its back during chemotaxis. Chemoattractant GPCRs control the actin cytoskeleton during cell migration. GPCR activation induces dissociation of the heterotrimeric G-protein into Galpha and Gbetagamma, which promote formation of new actin filaments via the Arp2/3 complex in migrating cells. The Arp2/3 complex is thought to be activated by Rac, and Elmo/Dock180 serves as a GEF for Rac activation. Recently, we identified a new Gbetagamma effector, ElmoE in Dictyostelium, and demonstrated that it is required for GPCR-mediated chemotaxis. Remarkably, ElmoE interacts with Gbetagamma and Dock-like proteins to activate the small GTPase Rac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin. Thus, ElmoE serves as the first direct link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton. We have revealed a novel pathway, consisting of GPCR, Gbetagamma, Elmo/Dock, Rac, and Arp2/3, that spatially guides the growth of dendritic actin networks in pseudopods of eukaryotic cells during chemotaxis. We propose that this pathway is evolutionary conserved in human cells. We will investigate this pathway in chemokine GPCR-controlled chemotaxis of human cells. (Yan et al, Developmental Cell, in revision).